Cigarette addiction is a major public health and economic problem and is the premier cause of preventable death. It is theorized that two major factors contribute to continued smoking and relapse: craving elicited by smoking cues (SCs) and craving elicited by nicotine withdrawal (WD). We have demonstrated that SC vs. nonSCs activate the mesocorticolimbic reward circuitry and that craving correlated with brain activity. Despite a robust overall cue effect, there was considerable individual variability in the brain response and in craving. As dopamine (DA) is a critical neurotransmitter for drug reward and is released by its signals, we hypothesize that genetically driven variation in DA transmission may account for the observed individual differences in brain and behavioral responses. In preliminary work we observed that smokers who are carriers of the `less efficient'DA transporter (DAT) gene 9 variable nucleotide tandem repeat (VNTR) show enhanced brain activation in our a priori regions during exposure to SCs compared to 10 VNTR homozygotes. This supports evidence that the DAT 9 allele is associated with lower expression of the DAT gene, which may reflect slower DA clearance, prolonging the reward message. We posit that genetic variability in this and other DA-ergic components may confer a susceptibility to SCs and/or WD symptoms that increase the probability of relapse. To begin to test this hypothesis we will utilize perfusion fMRI, smoking behavioral assays and a functional candidate gene association approach to examine the brain and behavioral activity of smokers under conditions of satiety and WD during exposure to SCs. Specifically, Aim 1) we will examine brain activity in 48 smokers who will undergo two counterbalanced scanning sessions, one while satiated and one [following a period of monitored] abstinence. Aim 2) we will examine naturalistic smoking behavior in response to SCs under both conditions. Smokers will rate their craving and WD before and after each session. Following each scan smokers will be given the opportunity to smoke during which data on latency to smoke and cigarette consumption will be collected, effectively linking brain and behavioral responses. Aim 3) we will examine the genetic contribution to the regional CBF changes and behavioral responses underlying WD- and SC-induced cigarette craving. DNA samples will be analyzed for allelic variance in dopaminergic genes, such as the DAT, responsible for DA reuptake;the catechol-o-methyltransferase (COMT) gene, involved in DA catabolism;and the DA receptor (D2 and D4) subtypes. One powerful feature of this proposal is to link brain, craving and genetics to actual smoking behavior, providing the foundation for future work during which treatment outcome can be examined with respect to gene variance, ultimately establishing a brain/behavioral/genetic endophenotype, such that smoking cessation treatments can be structured to meet individual needs and reduce the probability of relapse. PUBLIC HEALTH RELEVANCE: The proposed project will utilize perfusion fMRI, smoking behavioral assays and a functional candidate gene association approach of dopaminergic addictions-targeted polymorphisms to examine the brain and behavioral activity of smokers under conditions of satiety and withdrawal during exposure to smoking reminders. These studies will provide the foundation for future studies during which treatment strategies and treatment outcome and can be examined with respect to genetic subgroups of smokers. Ultimately, if a brain/behavioral/genetic endophenotype can be determined in advance of treatment, smoking cessation treatments can be structured to meet individual needs.